Thienopyrimidine and thienopyridine compounds and methods of use thereof

Abstract

The present disclosure provides compounds and methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules including but not limited to MLL1, MLL2 and MLL-fusion oncoproteins. Compounds of the disclosure may be used in methods for the treatment of a wide variety of cancers and other diseases associated with one or more of MLL1, MLL2, MLL fusion proteins, and menin.

What is claimed is: 
     
       1. A compound represented by the structure of Formula (4): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 R 1 , R 2 , R 4 , R 5 , R 8 , and R a  are independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 3-10  carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl come together to form a C 3-10  carbocycle or 3- to 10-membered heterocycle; and C 3-10  carbocycle and 3- to 10-membered heterocycle; wherein any C 3 -10 C 3-10  carbocycle and 3- to 10-membered heterocycle of R 1 , R 2 , R 4 , R 5 , R 8 , and R a  is independently optionally substituted with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 R 3  is selected from selected from hydrogen, —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO2 —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 3-10  carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl come together to form a C 3-10  carbocycle or 3- to 10-membered heterocycle; and C 3-10  carbocycle and 3- to 10-membered heterocycle; wherein any C 3-10  carbocycle and 3- to 10-membered heterocycle of R 3  is independently optionally substituted with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 R 6  is independently selected at each occurrence from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 3-10  carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl come together to form a C 3-10  carbocycle or 3- to 10-membered heterocycle; and C 3 -10o C 3-10  carbocycle and 3- to 10-membered heterocycle; wherein any C 3-10  carbocycle and 3- to 10-membered heterocycle of R 6  is independently optionally substituted with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , C(O)N(R 20 ) 2  —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 22 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 R 20  at each occurrence is independently selected from hydrogen; C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 30 , —SR 30 , —N(R 30 ) 2 , —N(R 30 )C(O)R 30 , —C(O)R 30 , —C(O)OR 30 , —C(O)N(R 30 ) 2 , —OC(O)R 30 , —S(O) 2 R 30 , —S(O) 2 N(R 30 ) 2 , —N(R 30 )S(O) 2 R 30 , —NO 2 , —P(O)(OR 30 ) 2 , —P(O)(R 30 ) 2 , —OP(O)(OR 30 ) 2 , and —CN; and 3- to 10-membered heterocycle and C 3-10  carbocycle; 
 R 30  at each occurrence is independently selected from hydrogen, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
 Y is N or C(R a ); 
 L is absent or selected from alkylene and heteroalkylene; 
 s is selected from 0, 1, 2, 3, and 4; 
 R 7a  is -G-V-R 9a :;  
 G is selected from alkylene, heteroalkylene, C 3-12  carbocycle, 3- to 12-membered heterocycle, and combinations thereof, wherein G is optionally substituted with one or more R 32  groups; 
 V is selected from a C 3-12  carbocycle, and 3- to 12-membered heterocycle; 
 
       wherein V is optionally substituted with one or more R 32  groups;
 R 9a  is selected from halogen, —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —N(R 20 )S(O) 2 R 20 , —NO 2 , =S, =N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 2-6  alkenyl, and C 2-6  alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 3-10  carbocycle, and 3- to 10-membered heterocycle; C 3-10  carbocycle and 3- to 10-membered heterocycle; or two R 32  on the same carbon atom can come together to form a C 3-10  carbocycle or 3- to 10-membered heterocycle, wherein each C 3-10  carbocycle and 3- to 10-membered heterocycle of R 32  is independently optionally substituted with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; and 
 R 32  at each occurrence is selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 3-10  carbocycle, and 3- to 10-membered heterocycle; C 3-10  carbocycle and 3- to 10-membered heterocycle; or two R 32  on the same carbon atom can come together to form a C 3-10  carbocycle or 3- to 10-membered heterocycle, wherein each C 3-10  carbocycle and 3- to 10-membered heterocycle of R 32  is independently optionally substituted with one or more substituents selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —OC(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —N(R 20 )S(O) 2 R 20 , —NO 2 , ═O, ═S, ═N(R 20 ), —P(O)(OR 20 ) 2 , —P(O)(R 20 ) 2 , —OP(O)(OR 20 ) 2 , —CN, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl. 
 
     
     
       2. The compound or salt of  claim 1 , wherein R 1  and R 2  are independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  haloalkenyl, C 2-6  alkynyl, and C 2-6  haloalkynyl. 
     
     
       3. The compound or salt of  claim 2 , wherein R 1  is selected from halogen, C 1-6  haloalkyl, C 2-6  haloalkenyl, and C 2-6  haloalkynyl. 
     
     
       4. The compound or salt of  claim 3 , wherein R 1  is selected from —CH 2 CF 3  and —CH 2 CHF 2 . 
     
     
       5. The compound or salt of  claim 2 , wherein R 2  is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C 1-6  alkyl, and C 1-6  alkoxy. 
     
     
       6. The compound or salt of  claim 5 , wherein R 2  is hydrogen. 
     
     
       7. The compound or salt of  claim 1 , wherein R 3 , R 4 , and R 5  are each hydrogen. 
     
     
       8. The compound or salt of  claim 1 , wherein R 6 , at each occurrence, is independently selected from halogen, —OH, C 1-6  alkyl, and C 1-6  alkoxy. 
     
     
       9. The compound or salt of  claim 1 , wherein R 8  is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  haloalkenyl, C 2-6  alkynyl, and C 2-6  haloalkynyl. 
     
     
       10. The compound or salt of  claim 9 , wherein R 8  is —CN. 
     
     
       11. The compound or salt of  claim 1 , wherein Y is N. 
     
     
       12. The compound or salt of  claim 1 , wherein L is absent. 
     
     
       13. The compound or salt of  claim 1 , wherein G is alkylene optionally substituted with one or more R 32  groups. 
     
     
       14. The compound or salt of  claim 13 , wherein G is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       15. The compound or salt of  claim 1 , wherein V is selected from azetidine, oxetane, piperidine, oxane, piperazine, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, morpholine, thiomorpholine, azepane, and homopiperazine, any one of which is optionally substituted with one or more R 32  groups. 
     
     
       16. The compound or salt of  claim 1 , wherein V is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, naphthalene, anthracene, quinoline, isoquinoline, quinoxaline, acridine, quinazoline, cinnoline, phthalazine, furan, dihydrofuran, thiophene, dihydrothiophene, imidazole, imidazoline, oxazole, oxazoline, pyrrole, dihydropyrrole, thiazole, dihydrothiazole, pyrazole, dihydropyrazole, isoxazole, dihydroisoxazole, isothiazole, dihydroisothiazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole, benzisoxazole, and benzothiazole, any one of which is optionally substituted with one or more R 32  groups. 
     
     
       17. The compound or salt of  claim 1 , wherein R 9a  is 
       
         
           
           
               
               
           
         
       
     
     
       18. A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       19. A pharmaceutical composition, comprising a compound of  claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
       20. A method for the treatment of a disease, of treating leukemia, a hematologic malignancy, a solid tumor cancer, glioma, or diabetes in a subject suffering therefrom comprising administering an effective amount of a compound of  claim 1 , or a salt thereof, to a the subject suffering from said disease, wherein said disease is leukemia, hematologic malignancies, solid tumor cancer, glioma, or diabetes. 
     
     
       21. A process of making a compound of claim 1 comprising mixing a compound of structure (a): 
       
         
           
           
               
               
           
         
       
       with a compound with the structure (b): 
       
         
           
           
               
               
           
         
       
       in the presence of a reducing agent. 
     
     
       22. The process of claim 21, wherein the reducing agent comprises boron. 
     
     
       23. The process of claim 22, wherein the reducing agent comprises sodium cyanoborohydride. 
     
     
       24. The process of claim 21, comprising preparing compound (b) by: mixing a compound with the structure (c): 
       
         
           
           
               
               
           
         
       
       with a compound with the structure (d): 
       
         
           
           
               
               
           
         
       
       in the presence of a base to obtain a product; and 
       subjecting the product to an acid to form compound (b). 
     
     
       25. The process of claim 24, wherein the acid is HCl.